Quinoline derivatives, process of synthesis and medicaments containing these derivatives

Abstract

The invention relates to derivatives corresponding to formula I: in which X is an alkyl-(CH 2 ) n — chain with n=0, 1 or 2, or O or N, Z is an aromatic which may contain heteroatoms chosen from O, N or S, as substitutions for the carbon atoms constituting said aromatic ring, this ring being substituted or otherwise with Rb, Rb represents 1 to 3 substituents chosen from —OH, —OR, —COOH, —COOR, —COH, —COR, —NH 2 , —NH(R), —NH(R,R′), —SH, —SR and CN, Ra is H or —(CH 2 ) n′ —Y, with n′=0, 1, 2 or 3 and Y and —CH 3 , —COOH, —COOR, —CN, —OH, —OR, SR, or an aryl group optionally substituted with Rb, R and R′ represent a linear or branched alkyl chain of 1 to 4 C, and their pharmaceutically acceptable salts. Application as active ingredient of medicaments inhibiting retrovirus integrases.

1 . A 2-carbamoyl-8-hydroxyquinoline-7-carboxylic acid compound or its pharmaceutically acceptable salt, wherein said compound corresponds to formula I:  
     
       
         
         
             
             
         
       
     
     in which 
 X represents an alkyl-(CH 2 ) n — chain in which n is equal to 0, 1 or 2, O, or N,  
 Z represents an aromatic ring which may contain heteroatoms chosen from O, N or S, as substitutions for the carbon atoms constituting said aromatic ring, it being possible or otherwise for this ring to be substituted with Rb,  
 Rb represents 1 to 3 identical or different substituents chosen from the group —OH, —OR, —COOH, —COOR, —COH, —COR, —NH 2 , —NH(R), —NH(R,R′), —SH, —SR and CN,  
 Ra represents a hydrogen atom or a group —(CH 2 ) n′ —Y, for which n′ is equal to 0, 1, 2 or 3 and Y represents —CH 3 , —COOH, —COOR, —CN, —OH, —OR, SR, or an aryl group optionally substituted with Rb,  
 R and R′, which are identical or different, represent a linear or branched alkyl chain of 1 to 4 carbon atoms.  
 
   
   
       2 . A 2-carbamoyl-8-hydroxyquinoline-7-carboxylic acid compound, chosen from 2-(3,4-dihydroxybenzylcarbamoyl)-8-hydroxyquinoline-7-carboxylic acid and 2-(2,4-dihydroxybenzylcarbamoyl)-8-hydroxyquinoline-7-carboxylic acid, and a sodium salt of said compound.  
   
   
       3 . A biological reagent comprising a compound as defined in  claim 1 .  
   
   
       4 . A method for inhibiting retrovirus integrase in a patient comprising administering a compound as defined in  claim 1  to a patient in the need thereof.  
   
   
       5 . A method for treating HIV comprising administering a compound as defined in  claim 1  to a patient in the need thereof.  
   
   
       6 . A combination comprising a compound as defined in  claim 1  and an anti-HIV medicament, together with a pharmaceutically acceptable vehicle.  
   
   
       7 . A combination according to  claim 6 , wherein said anti-HIV medicament is chosen from medicaments endowed with an inhibition effect toward reverse transcriptase and/or protease.  
   
   
       8 . A compound of formula (II):  
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  are identical or different and represent alkyl radicals of 1 to 4 C.  
   
   
       9 . A biological reagent comprising a compound as defined in  claim 2 .  
   
   
       10 . A method for inhibiting retrovirus integrase in a patient comprising administering a compound as defined in  claim 2  to a patient in the need thereof.  
   
   
       11 . A method for treating HIV comprising administering a compound as defined in  claim 2  to a patient in the need thereof.  
   
   
       12 . A combination comprising a compound as defined in  claim 2  and an anti-HIV medicament, together with a pharmaceutically acceptable vehicle.  
   
   
       13 . A combination according to  claim 12 , wherein said anti-HIV medicament is chosen from medicaments endowed with an inhibition effect toward reverse transcriptase and/or protease.